Background: There
has been an explosion in the development of hormonal therapies for the treatment
of breast cancer. Several new agents have been approved for the treatment of
breast cancer in the metastatic setting, and trials are ongoing in the adjuvant
and prevention setting to improve hormonal therapy for the prevention and treatment
of breast cancer.
Methods: The
literature on new hormonal therapies for the treatment of breast cancer is reviewed,
with an emphasis on newer agents.
Results:
Two antiestrogens are now approved in the United States for the treatment of
metastatic breast cancer. Other antiestrogens have activity in metastatic breast
cancer as well as in osteoporosis. Newer pure antiestrogens may overcome resistance
to tamoxifen. Several aromatase inhibitors are available for the treatment of
metastatic breast cancer.
Conclusions:
Many hormonal agents are now available for both adjuvant and advanced disease
settings. Developments will depend on clarifying mechanisms of resistance to
antiestrogens and identifying new classes of agents that lack cross-resistance
to standard therapy.
Introduction
Tamoxifen has been the preferred antiestrogen hormonal
treatment for breast cancer for the last 30 years.1 It is a nonsteroidal
antiestrogen with tissue selective estrogen agonist and antagonist activity.
Tamoxifen exerts beneficial estrogenic effects on bone density and serum lipids
but unfavorable estrogenic effects in the endometrium.2-4 The antiestrogen
effects of tamoxifen in the breast led to its use in the treatment of breast
cancer. It is the established therapy to consider in all stages of breast cancer.
The finding of endometrial cancer resulting from tamoxifen treatment has led
researchers to investigate new agents that retain favorable estrogenic properties
in specific tissues and display antiestrogen activity on the endometrium. Such
research has generated the concept of selective estrogen receptor modulators
(SERMs) that mediate either estrogen agonist or estrogen antagonist effects
in different tissues. The future of SERMs will depend on a better understanding
of the various mechanisms of estrogen receptor (ER) modulation and whether they
induce the wanted effects in specific tissues or organs.
There are at least two different types of ERs.5
Alpha receptors predominate in the breast and uterus, and beta receptors predominate
in the bone and blood vessels. In addition, many proteins interact with these
receptors to act as coactivators or co-repressors at the receptors. To further
complicate matters, at least 50 different transcription-activating factors modulate
the effects of estrogen on its target genes.5 The development of
new therapies will be facilitated with a better understanding of the interactions
of the ERs, coactivator and corepressor proteins, and transcription-activating
factors. Agents should become available that specifically interrupt resistance
pathways to standard hormonal treatment or bypass these pathways so that effective
responses to therapy can be maintained. New developments are underway for both
antiestrogen therapies and aromatase inhibitor therapies. Table 1 lists selected
new agents in development. Some are approved for the treatment of metastatic
breast cancer, and several are involved in ongoing studies in the adjuvant setting.
Furthermore, some of these agents have not been developed primarily for treatment
of breast cancer but are being investigated specifically for the prevention
of the disease. The partial agonist/antagonist antiestrogen agents have added
benefits of preventing osteoporosis and lowering lipid because of the estrogen
agonist effects in these tissues. The aromatase inhibitors are not expected
to provide these benefits. Compared with antiestrogens, however, they may provide
a lower risk of thromboembolic events with no risk of added endometrial proliferation
leading to endometrial cancer. To improve survival from breast cancer and other
causes in the metastatic, adjuvant, and prevention settings, we now need to
determine how best to use these new agents in terms of sequence and as single
or combination drug therapies.
|
Table
1. — New Hormonal Therapies in Breast Cancer
|
| |
Nonsteroidal |
Steroidal |
| Antiestrogens: |
Toremifene
(Fareston) |
ICI
182,780 (Faslodex) |
| |
Idoxifene |
EM-800 |
| |
Droloxifene |
|
| |
TAT-59 |
|
| |
Zindoxifene |
|
| |
Trioxifene
|
|
| |
Raloxifene
(Evista) |
|
| |
|
|
| Aromatase
Inhibitors: |
Anastrozole
(Arimidex) |
Formestane
(Lentaron) |
| |
Letrozole
(Femara) |
Exemestane |
| |
Vorozole
(Rivizor) |
|
New Developments With Tamoxifen
Tamoxifen has breast cancer prevention effects.
The National Surgical Adjuvant Breast and Bowel Project (NSABP) trial recruited
more than 13,000 women at high risk of developing breast cancer.6
The Gail model was used to calculate their risk of developing breast cancer.7
This model incorporates family history, age, previous breast biopsies, and other
established estrogen-mediated risk factors such as age at first live birth,
parity, and age of menarche. Women aged 35 to 65 years were randomly allocated
to receive either tamoxifen 20 mg/day or placebo for 5 years. The results of
this study indicate that tamoxifen reduced the incidence of breast cancer in
this high-risk population by 49%.8 The drug was well tolerated, and
the dropout rate due to side effects was low. Other clinical endpoints included
measures of bone fracture rate, cardiac mortality, endometrial cancer, and thromboembolic
events. The increased rate of endometrial cancer was similar to that reported
in breast cancer adjuvant treatment trials.4,9 At 66 months of follow-up,
the cumulative incidence of endometrial cancer was 13 per 1,000 women. There
were no deaths from endometrial cancer in the tamoxifen treatment arm since
these were early-stage tumors. Moreover, the incidence of bone fractures in
the hip, spine, and lower radius was decreased by 19%, but thromboembolic events
increased in women over 50 years of age. Cardiac mortality in the tamoxifen
group was similar to that in the placebo group, but the study did not have the
statistical power to show a difference in events that would have a significant
impact on survival. As a result of this study, tamoxifen was approved in the
United States for the prevention of breast cancer in women at increased risk
of developing breast cancer. Before prescribing this drug to healthy women,
the risks and benefits of tamoxifen should be discussed with them so that they
are aware of possible effects.
New Antiestrogens
Toremifene
Toremifene is a chlorinated analogue of tamoxifen
and has similar site-specific estrogen and antiestrogen activity.10
Preclinical studies report that toremifene may result in less DNA adduct formation
in the endometrium than tamoxifen.11 DNA adduct formation is thought
to be an important mediator of genetic changes and cellular progression to cancer.12
However, toremifene has been shown to have comparable stimulatory effects as
tamoxifen on human endometrial cancers in athymic mice.13 Tomas and
colleagues14 investigated the effects of toremifene and tamoxifen
on postmenopausal endometrium in breast cancer patients receiving therapy for
12 months. Parameters that included endometrial thickness, cellular proliferation,
and uterine fibroids and polyps were similar in the two treatment groups. These
data suggest that toremifene has estrogenic effects in the uterus that are comparable
to tamoxifen and that toremifene may be associated with an increased risk of
endometrial cancer. The actual incidence of endometrial cancer associated with
toremifene treatment will be determined in the present ongoing adjuvant trials.
Saarto and colleagues15 have evaluated changes in lipid levels from
toremifene and tamoxifen during the first year of use. Toremifene and tamoxifen
produced similar changes with one exception: toremifene resulted in a rise in
serum HDL levels by 14% compared to a 5% decrease in serum HDL levels in women
taking tamoxifen. The significance of this finding is unclear. Following reports
of several phase III trials demonstrating that toremifene is as efficacious
as tamoxifen in the first-line treatment of metastatic breast cancer, toremifene
was approved for the front-line treatment of metastatic breast cancer in ER-positive
or ER-unknown patients. The Eastern European trial16 and the Nordic
trial17 each included more than 400 postmenopausal women with metastatic
breast cancer. The larger US trial,18 which included 648 postmenopausal
women with metastatic breast cancer, compared tamoxifen (20 mg/day) vs a standard
dose of toremifene (60 mg/day) and a higher dose of toremifene (200 mg/day)
and found a similar response rate (19.1% vs 21.3% vs 22.6%, respectively). Similarly,
the Eastern European trial16 tested two different dose levels of
toremifene at 60 mg and 240 mg daily. Responses ranged from 30% to 37% with
no statistically significant differences reported in response rates. In all
three trials, overall response, median duration of response (16 to 26 months),
and median survival (23 to 38 months) were not significantly different from
those seen with tamoxifen. The most common adverse events (hot flashes, sweating,
nausea and/or vomiting, vaginal discharge, dizziness, edema, vaginal bleeding,
liver function abnormalities, ocular changes, and thromboembolic events) occurred
with similar frequency with the two agents. To date, these phase III trials
have not demonstrated greater benefit from higher doses of toremifene. Multiple
phase II metastatic breast cancer trials investigating toremifene in tamoxifen-refractory
patients demonstrate cross-resistance to tamoxifen based on low response rates.
The largest of these trials reported by Vogel and colleagues found an overall
response rate of 5%.19-24
Toremifene is now being compared with tamoxifen
in adjuvant trials. The first adjuvant trial to open in 1992 was the Finnish
trial,25 which compared use of either toremifene 40 mg/day or tamoxifen
20 mg/day for 3 years in postmenopausal women with node-positive breast cancer.
The results at three years of median follow-up demonstrate no significant differences
in breast cancer recurrence rates and adverse events in the two treatment arms.25
Other effects such as endometrial thickening, cytologic changes, DNA adduct
formation, serum lipid levels, bone density changes, and ocular effects are
being monitored to determine any potential benefits from toremifene compared
to tamoxifen.
Idoxifene
Idoxifene is an antiestrogen in clinical development
for several different treatment settings. It was designed with an iodine atom
at the 4 position of tamoxifen to prevent metabolic activation to 4-hydroxytamoxifen
and an additional pyrrolidine side chain to decrease carcinogenic potential
associated with demethylation.26 In animal models, idoxifene use
decreased uterine weight, prevented bone loss, and lowered serum cholesterol
levels.27 Coombes and colleagues28 reported on a phase
I trial of idoxifene in 20 metastatic breast cancer patients who had previously
been treated with tamoxifen. Using a dose between 10 to 60 mg orally per day,
the drug was well tolerated with only mild toxicities, and the patients had
a partial response rate and stable response rate of 14% and 29%, respectively,
ranging from 1.4 to 14 months.
Droloxifene
Droloxifene is a monohydroxylated metabolite of tamoxifen.
This 3-hydroxy-tamoxifen has some antiestrogenic effects in the uterus and maintains
bone density in animal models.29,30 There have been multiple phase
II trials in metastatic breast cancer.31-33 The largest was reported
by Rauschning and Pritchard,34 who investigated dosages of droloxifene
ranging from 20 to 100 mg/day. Responses in the 269 women assessable for response
revealed a 30% response in the 20-mg arm compared to a 47% response in the 40-mg
arm and a 44% response in the 100-mg arm. Response rates favored higher doses
(40 mg vs 20 mg: P=0.02; 100 mg vs 20 mg: P=0.04). The median response duration
was 12 months in the 20-mg arm, 15 months in the 40-mg arm, and 18 months in
the 100-mg arm. In all of these trials, droloxifene was well tolerated, and
the side effects were similar to that of tamoxifen.
TAT-59
TAT-59 is a prodrug that requires dephosphorylation
to become the active metabolite of tamoxifen, 4-hydroxytamoxifen. This agent
has a high affinity for the ER.35 A phase II trial has been reported
in abstract form comparing the efficacy of tamoxifen with TAT-59 in the first-line
treatment of metastatic breast cancer.36 The response rate was assessed
in 193 patients given 20 mg/day of either agent for more than 12 weeks. The
total response rate was 30% in the TAT-59 arm compared to 26.5% in the tamoxifen
arm. The responses, median duration of response, and survival were similar for
both treatments. Adverse reactions were mild, and TAT-59 had comparable toxicities
to tamoxifen.
Zindoxifene
Zindoxifene is an indole derivative of tamoxifen.
A phase I/II trial of zindoxifene was reported by Stein and colleagues37
from the United Kingdom. The doses ranged from 10 mg/day to 100 mg/day orally.
Twenty-eight women with metastatic breast cancer who had previously received
endocrine therapy were treated with no objective responses; 20% had disease
stabilization for 5 months. Nausea was the dose-limiting toxicity in 50% of
patients at a dose of 80 mg/day.
Trioxifene
Trioxifene is an antiestrogen that was developed
in the early 1970s. This agent has been studied in advanced breast cancer and
had considerable side effects including a 41% incidence of leukopenia and a
31% incidence of nausea.38 Due to the side effects of trioxifene
and the lack of increased efficacy when compared to tamoxifen, this agent has
not been clinically developed further.
Raloxifene
Raloxifene is a nonsteroidal benzothiophene derivative
that binds to the ER and has been classified as a SERM because it has been shown
to have antiestrogenic effects in the uterus and breast as well as estrogenic
effects on bone and cholesterol.39-42 A phase II trial was reported
comparing the efficacy of raloxifene in metastatic breast cancer patients who
were refractory to tamoxifen. A dose of 200 mg/day was chosen after reviewing
data from phase I studies. The drug was given for up to 8 months; however, no
objective responses were observed.43 Because of the beneficial effects
of raloxifene in bone density and serum lipids, raloxifene was studied in postmenopausal
women with no history of breast cancer. The aim was to determine if raloxifene
was a reasonable alternative agent for women who wished to avoid estrogen replacement
therapy because of the potential increased risk of breast cancer. An osteoporosis
prevention trial was initiated investigating raloxifene, and postmenopausal
bone mineral density increased by by 2% to 3% compared to placebo after two
years of use.44 Raloxifene was approved in the United States for
the prevention of osteoporosis in postmenopausal women after review of the data
from three large multicenter trials (Eli Lilly Pharmaceuticals data on file,
1998). This antiestrogen also produced lipid profile changes similar to those
with tamoxifen.45 Raloxifene did not cause endometrial thickening
or cellular proliferation and did not cause symptoms of estrogen effects on
the endometrium such as vaginal bleeding.44 The Multiple Outcomes
of Raloxifene Evaluation (MORE) trial was first reported at the American Society
of Clinical Oncology (ASCO) meeting in May 1998. In this trial, 7,705 postmenopausal
women with a history of osteoporosis were recruited. All patients received 1,200
mg/day of calcium and were allocated to receive raloxifene at 60 mg/day or 120
mg/day or placebo. At a median follow-up of two years, the incidence of vertebral
fractures was reduced by 44% in the women taking raloxifene compared to placebo,
and there was no difference in vertebral fractures in the standard vs high-dose
raloxifene group.46 The incidence of ER-positive breast cancer was
74% lower in the raloxifene group compared with the placebo group.47
As in the tamoxifen breast cancer prevention trial (NSABP P-1), the protection
was seen only in the group of women who developed ER-positive breast cancers.
The incidence of endometrial cancer was not increased in either of the raloxifene
treatment groups when compared to the placebo group. In fact, the incidence
of uterine cancer was found to be 62% lower; however, this finding did not reach
statistical significance (P=0.232).47 These findings have prompted
further investigation of raloxifene as a breast cancer preventive agent in a
prospective fashion and in comparison to tamoxifen. Currently, there is no approved
indication for raloxifene in the management of any phase of breast cancer. Use
of raloxifene in the treatment of breast cancer should be restricted to participation
in the NSABP P-2 breast cancer prevention trial.
New Pure Antiestrogens
Two steroidal antiestrogens have been developed
that have pure antiestrogen activity in all tissues.48,49 ICI 164,384 has been studied extensively in the
preclinical setting; however, the more potent ICI 182,780 (Faslodex) is being
studied in human clinical trials in metastatic breast cancer. Faslodex is not
orally bioavailable and must be given intramuscularly on a monthly basis. An
initial phase II trial in metastatic breast cancer
50 reported promising results in a tamoxifen-refractory
population. This small trial of 19 women demonstrated that monthly administration
of Faslodex at 250 mg intramuscularly provided a partial response rate of 37%
and a stable disease response of 32% with a median duration of response of 26
months. Thus, a lack of cross-resistance with tamoxifen was apparent in 69%
of the patients. Menopausal side effects did not appear to be increased by Faslodex
therapy. Preclinical data demonstrated that Faslodex does not cross the blood-brain
barrier and suggests that Faslodex might have fewer side effects in terms of
menopausal symptoms than other antiestrogens.49
Another class of novel antiestrogen compounds inhibit
estradiol-mediated action of the ERs. EM-652 is the active metabolite of the
prodrug EM-800 and is available in oral form. Both are potent nonsteroidal pure
estrogen antagonists of both alpha and beta ER subtypes.51 EM-652
is 20 times more potent than Faslodex or droloxifene and is 400 times more potent
than toremifene in displacing the 17 beta-estradiol from the rat uterine ER.52
Thus, EM-652 has the highest known affinity to the ER when studied in competition
receptor assays in animal models. No significant binding occurred to the rat
uterine progesterone receptor. Preclinical studies have shown that EM-652 blocks
ras-mediated induction of ER transcriptional activity that normally occurs
in the presence of estrogen.51 A small phase II trial is in progress
in metastatic breast cancer to not only investigate the efficacy of EM-800,
but also address the potential lack of cross resistance with tamoxifen because
of its potent antiestrogen properties.
New Nonsteroidal Aromatase Inhibitors
Aromatase inhibitors have a different mechanism
of action than antiestrogens and have been used primarily in the postmenopausal
population. Aromatase is present in several peripheral tissues including the
breast, muscle, liver, and adipose. Aromatase is important in the production
of peripheral estrogen. The more important mechanism of action may be the intratumoral
aromatase action.53,54 The first aromatase inhibitor to become commercially
available was aminoglutethimide. Aminoglutethimide has demonstrated activity
in the metastatic breast cancer setting (response rates of 20% to 40%) when
compared to established second-line therapy with megestrol acetate.55-57
It produces effects on glucocorticoid production and is now used infrequently
in the clinical setting due to side effects.
Two new aromatase inhibitors with more potent aromatase
inhibition than aminoglutethimide — anastrozole and letrozole — are
now approved in the United States for second-line treatment of metastatic breast
cancer in postmenopausal women. Anastrozole and letrozole have been investigated
in tamoxifen refractory patients. Ongoing trials are comparing these agents
to tamoxifen as front-line therapy for metastatic breast cancer.
Anastrozole
Anastrozole is an achiral triazole derivative that
is similar to aminoglutethimide.58 However, unlike aminoglutethimide,
anastrozole does not require supplementation with corticosteroid treatment because
it is more selective for the aromatase enzyme and does not disrupt adrenal corticoid
production.59 Recently, data were pooled from two phase III trials
of similar design and included 764 patients.60 Postmenopausal women
with metastatic breast cancer who had progressed on tamoxifen were eligible.
Two different dose levels of anastrozole were tested. Anastrozole given at 1
mg/day and 10 mg/day was compared to standard-dose megestrol acetate (40 mg
orally four times daily). The different treatment arms demonstrated no difference
in response rate or time to disease progression. However, a benefit in terms
of survival was seen in the anastrozole group compared to the group on megestrol
acetate. At a median follow-up of 31 months, anastrozole demonstrated a statistically
significant survival advantage over megestrol acetate (hazard ratio 0.78, P<0.025).
The group using 10 mg/day showed no advantage in response rate or survival over
the group using 1 mg/day. The median time to death in the 1-mg anastrozole,
10-mg anastrozole, and megestrol acetate groups were 26.7, 25.5, and 22.5 months,
respectively. Overall, treatment with anastrozole was better tolerated than
megestrol acetate, and the withdrawal rate due to adverse events was higher
in the megestrol acetate group (4% vs 1.9%). Further analysis revealed that
those patients who had a partial or complete response or who had stabilization
of disease for at least six months had a longer time to disease progression
in the anastrozole group than the megestrol group. The differences in time to
disease progression in this subset of responders and the differences in withdrawal
due to side effects are thought to account for the survival advantage seen in
the anastrozole group.
Letrozole
Letrozole, a triazole derivative, was the next aromatase
inhibitor to become commercially available. Two phase III trials involving postmenopausal
women with metastatic breast cancer who had progressed or relapsed on tamoxifen
have been published.61,62 The first trial, which compared letrozole
to megestrol acetate, showed an improved response rate and an improved time
to treatment progression compared to the group receiving megestrol acetate.61
The 2.5 mg/day dose of letrozole had a higher response rate (23.6%) than the
0.5 mg/day dose (12.8%). Time to progression and time to treatment failure were
longer with the 2.5 mg/day dose of letrozole, and there was a suggestion of
improvement in survival that did not reach statistical significance. The second
trial, which compared letrozole to the first-generation aromatase inhibitor
aminoglutethimide, showed a trend in favor of the 2.5 mg/day letrozole arm in
overall response rate.62 The overall survival was superior in the
group that received 2.5 mg/day of letrozole compared to the aminoglutethimide
group (28 months vs 20 months, P=.002). The overall survival was significantly
longer in the group using 2.5 mg/day of letrozole compared to the group using
0.5 mg/day of letrozole (28 months vs 21 months, P=0.04). This improved dose-response
effect led to the approval of letrozole at the higher dose of 2.5 mg/day. In
both trials, letrozole was better tolerated than the comparison agent.
Vorozole
Vorozole is an aromatase inhibitor similar to anastrozole
and letrozole. Results in the second-line treatment setting for postmenopausal
women with metastatic breast cancer were recently reported. The first report
compared vorozole 2.5 mg/day to megestrol acetate 40 mg four times per day.63
Response rates and survival were similar in the two groups. The second trial
compared vorozole 2.5 mg/day with aminoglutethimide 250 mg twice per day. The
response rate and survival were similar, but vorozole was better tolerated.64
Table 2 compares the three third-generation aromatase
inhibitors compared to megestrol acetate in terms of response rate and median
overall survival as reported in each of the separate second-line metastatic
breast cancer treatment trials that evaluated efficacy.
Table
2. — Results From Third-Generation Aromatase Inhibitors
Used as Second-Line Treatment in Metastatic Breast Cancer* |
| |
Anastrozole
(1 mg)60 |
Letrozole
(2.5 mg)61,62 |
Vorozole
(2.5 mg)63,64 |
| Number
of Patients |
764 |
551 |
452 |
| Median Follow-up |
31
months |
33
months |
NA |
| Response
Rate (CR + PR) |
12.6% |
23.6%
(P=0.04)** |
9.7% |
| Median Duration of
Response |
NA |
NR
(P=0.02)** |
18.2
months |
| Time
to Progression |
4.8
months |
5.6
months |
2.7
months |
| Median Survival Time |
26.7 months
|
25.3
months |
26
months |
| Overall Survival |
HR
0.78 (P<0.02)** |
HR
0.82 (P=0.15) |
HR
1.06 (P=0.56) |
|
* These agents have not been compared directly with each other. The results
are from trials of each drug compared to megestrol acetate.
** Statistically significant.
CR = complete response
PR = partial response
HR = hazard ratio
NA = not available
NR = not reached |
The steroidal aromatase inhibitors are exciting new
agents because they appear to lack cross-resistance with the other nonsteroidal
agents discussed above. These agents compete with the natural substrate for
aromatase enzyme action and bind irreversibly to the enzyme leading to its inactivation.65
This mechanism of action differs from anastrozole and letrozole, and these agents
are quite specific because they bind to the active site of the enzyme.
Formestane
Formestane is now approved in Europe for the treatment
of metastatic breast cancer in women who have failed tamoxifen therapy. Formestane
is not orally bioavailable and is given intramuscularly each month. It has been
tested in the front-line, second-line, third-line and even fourth-line setting
in metastatic disease and has been shown to have high response rates. The response
rate in the third- and fourth-line setting was 22% with a median response duration
of 10 months. This result was surprising considering that this group of 147
women had previously failed multiple hormonal therapies including aminoglutethimide.66
Further data from these trials include the lower rate of thromboembolic events
associated with formestane in comparison to tamoxifen or megestrol acetate.67
Exemestane
The newest steroidal aromatase inhibitor to be
developed is exemestane. This drug has been tested in metastatic breast cancer
in the third-line treatment setting with similarly encouraging response rates
as formestane. In a phase II trial of exemestane 25 mg/day given orally in postmenopausal
women with metastatic breast cancer who had progressed on tamoxifen and megestrol
acetate, the response rate was 11%. By including stabilization of disease for
at least six months as a response category, the overall incidence of benefit
increased to 29%. The median duration of effect, including stabilization of
disease, was 11 months.68 In another trial involving 241 postmenopausal
women who had previously been treated with either aminoglutethimide, vorozole,
or letrozole, the response rate, including stability of disease, after treatment
with exemestane 25 mg/day was 25%.69 Time to progression was 15 weeks.
In the second-line treatment setting for metastatic breast cancer, exemestane
25 mg/day vs standard-dose megestrol acetate treatment in 128 postmenopausal
women demonstrated a response rate of 28%. By including stabilization of disease
for at least six months, the response rate increased to 47%. The median duration
of response was 14 months.70 These new data on the steroidal aromatase
inhibitors suggest a lack of cross-resistance to tamoxifen and other nonsteroidal
aromatase inhibitors.
Future Directions
Clinical trials are in progress evaluating new
hormonal agents for the treatment and prevention of breast cancer. The new steroidal
antiestrogens are under further clinical development in the metastatic setting.
Faslodex (ICI 182,780) is being studied in several ongoing large phase III trials
comparing its efficacy to anastrozole in the second-line treatment setting and
in the first-line treatment setting with tamoxifen. A small, unpublished phase
II trial investigating EM-800 in the metastatic breast cancer setting in women
who had progressed on tamoxifen showed encouraging results and thus implies
a lack of cross-resistance with tamoxifen. EM-800 will be studied in a large
trial comparing its efficacy to anastrozole in the second-line treatment setting
of metastatic breast cancer.
Adjuvant trials of hormone therapy are ongoing.
The International Breast Cancer Study Group has opened two trials comparing
the efficacy of tamoxifen to toremifene in postmenopausal and perimenopausal
women given in combination or sequentially after adjuvant chemotherapy. A US
trial for postmenopausal women has opened to compare the efficacy of tamoxifen
with toremifene for the adjuvant treatment of early stage breast cancer. This
trial excludes treatment with chemotherapy. The only premenopausal trial in
progress compares the efficacy of tamoxifen to toremifene for five years given
after four cycles of adjuvant chemotherapy with doxorubicin plus cyclophosphamide.
Several adjuvant trials are comparing the efficacy
of various aromatase inhibitors with tamoxifen. Two large-scale trials using
anastrozole are in progress. One study is comparing anastrozole plus tamoxifen
vs each single agent for a five-year duration. The second involves studying
two years of adjuvant tamoxifen, then three years of either tamoxifen or anastrozole.
Letrozole is being studied in a similar fashion to anastrozole including a comparison
of the efficacy of single-agent therapy and also an evaluation of sequential
therapy. Patients who have taken tamoxifen for five years will receive letrozole
or placebo for another five years. Finally, investigators are organizing a trial
to evaluate tamoxifen treatment for two to three years followed by randomization
to either tamoxifen or exemestane for a total of five years’ duration of adjuvant
therapy. These adjuvant trials will determine if these newer hormonal agents
are superior to standard tamoxifen therapy or if a combination of agents is
more effective than tamoxifen alone.
Many of the new antiestrogens have been identified
as potential agents for the prevention of both osteoporosis and breast cancer.
Because of the favorable effects seen in selective tissues, the SERM droloxifene
will be investigated in the treatment of osteoporosis in postmenopausal women.
A primary breast cancer prevention trial that has been organized by the NSABP,
which compares the efficacy of tamoxifen vs raloxifene (STAR trial), will open
in 1999. Approximately 22,000 postmenopausal women will be treated for five
years in a double-blind fashion. Risk factors for breast cancer will be determined
using the Gail model, similar to the design of the NSABP Tamoxifen Prevention
Breast Cancer Trial.8 Other endpoints of these trials, eg, quality-of-life
measures, menopausal side effects, other life-threatening side effects, and
causes of mortality other than breast cancer, will be important in determining
the best hormonal therapy for the adjuvant treatment and the prevention of breast
cancer. Future development of new classes of hormonal agents such as aromatase
inhibitors will improve treatment strategies for resistance to therapy. Antiestrogen
agents with more potent affinity for the ER and agents that are able to interfere
with ER-mediated transcriptional activity are under development with the hope
of overcoming tamoxifen resistance.
Conclusions
The burgeoning interest in the application of hormone
therapy on preventing and treating breast cancer is being assisted by increasing
understanding of the biologic processes that govern hormonal action. The advent
of several new drugs bodes well for the future improvements in clinical outcomes
from this clinical approach.
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From the Comprehensive Breast Program, H. Lee Moffitt Cancer Center & Research
Institute at the University of South Florida, Tampa, Fla.
Address reprint requests
to Susan E. Minton, DO, H. Lee Moffitt Cancer Center & Research Institute,
12902 Magnolia Drive, Suite 3157, Tampa, FL 33612.
Dr Minton receives support
from Schering Pharmaceuticals, Inc, for the Fareston adjuvant multicenter clinical
trial.
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